PROJECT SUMMARY/ABSTRACT Glioblastoma (GBM) is the most lethal primary brain tumor with median survival of up to 20 months despite aggressive interventions including surgery, radiation, and chemotherapy. An established immunosuppressive microenvironment facilitating tumor progression is a major factor contributing to the aggressiveness of GBM. Efforts are underway to develop immunotherapies against GBM, and current strategies primarily focusing on activation of anti-tumor T cells have thus far been ineffective. This suggests that there is a need to gain mechanistic insight into the GBM immune architecture, which consists of various immunosuppressive cell types including tumor-associated macrophages (TAMs) and monocytic-/granulocytic- myeloid-derived suppressor cells (mMDSCs and gMDSCs). In pre-clinical models, I have demonstrated that the relative frequencies of these myeloid populations in tumors and the peripheral circulation are different in males, who constitute 60% of GBM patients and have a worse prognosis, than females. The myeloid compartment is further impacted by the corticosteroid dexamethasone (DEX), an immunomodulatory drug used clinically to limit cerebral edema but that dampens radiation and immunotherapy response. Based on these observations, I hypothesize that sexual dimorphism in anti-tumor immunity determines GBM prognosis and treatment response, which is further altered by DEX usage. Specific Aim 1 will test the hypothesis that sex differences in GBM immunity contribute to disease prognosis. Sub-Aim 1A will delineate the role of intrinsic factors versus soluble mediators in the sexual dimorphism of GBM immune response by investigating the immune infiltration pattern in bone marrow chimeras and mice treated with sex hormone supplements or antagonists. Sub-Aim 1B will investigate the differential role of systemic versus local immune suppression between females and males by characterizing the expression profiles of MDSCs and TAMs and selectively targeting these populations. Specific Aim 2 will test the hypothesis that inhibiting immunosuppressive myeloid cells mitigates the negative effects of DEX on radiotherapy and checkpoint inhibitor response. The role of MDSCs/TAMs in DEX-mediated therapeutic resistance will be examined by depleting these populations during chronic DEX administration prior to or post radiation and checkpoint inhibition therapy. This project has the potential to develop more effective immunotherapy approaches by exploring variations in the tumor microenvironment. These insights can inform the development of novel immunotherapeutics while also improving the implementation of existing treatment modalities by addressing gaps in our understanding of GBM management strategies. Such results are broadly applicable to other cancers and can accelerate research to improve patient welfare, leading to advanced treatment opportunities. The studies outlined in this fellowship will provide me an opportunity to gain experience in GBM research to complement my experience in tumor immunology and allow me to continue my training though additional workshops, scientific meetings and mentorship opportunities, thereby preparing for an independent research career.